In neuropathic pain, which predominates in inveterate pain, even in the absence of stimuli to nociceptors due to tissue damage, persistent, unbearable, burning pain is caused, and in many cases, it may be complicated with paroxysmal pain. Additionally, hypoesthesia may occur in pain locations, and allodynia, in which pain is initiated by a slight stimulus which does not normally provoke pain, may often be observed. Clinically, these characteristic symptoms are mixed in the individual diseases. The International Association for the Study of Pain defines neuropathic pain as pain caused by a primary lesion or dysfunction of the nervous system, and the nervous system includes the peripheral nervous system and the central nervous system. Specifically, neuropathic pain can be related to peripheral nerve disorders (e.g., diabetes, alcoholic and other drug poisoning, and amyloidosis), amputation, posterior rhizotomy, brachial plexus avulsion injuries, spinal cord injuries, multiple sclerosis, the Parkinsonian syndrome, etc., and can be postherpetic neuralgia, central postapoplectic pain (so-called thalamic pain), etc. That is, neuropathic pain is caused by organic changes or dysfunction of the nervous system due to external injuries to the peripheral or central nervous system itself, infection, ischaemia, etc.
Morphine, which is widely used for treating pain, does not have a sufficient effect on the treatment of neuropathic pain, and also neuropathic pain is often resistant to opioid analgesics. Under the circumstances, development of effective therapeutic agents for inveterate pain including neuropathic pain has been desired. Examples of known therapeutic methods include surgical treatment, such as therapeutic spinal cord stimulation and dorsal root entry zone lesions, and chronic intrathecal administration of Baclofen, which is a γ-aminobutyric acid (GABA) receptor agonist, and ketamine, which is an N-methyl-D-aspartate (NMDA) receptor antagonist. However, since these methods are highly invasive, less invasive therapeutic methods have been desired, and thus it is important to develop new drugs effective against neuropathic pain.
On the other hand, although Japanese Patent No. 2525552 discloses morphinan derivatives having opioid κ-receptor agonist activity and analgesic action, the therapeutic effects of these compounds on neuropathic pain are not disclosed.
An animal model which shows the same clinical symptoms as those of human neuropathic pain is essential to the development of effective new drugs for neuropathic pain. Currently, with respect to the neuropathic pain animal model, although cutting and ligature of the peripheral nerve (G. J. Bennet & Y. K. Xie, Pain, 33: 87-107, 1988) or damage to the spinal cord (J. X. Hao, Pain, 45: 175-185, 1991) are conducted, complex operations must be performed for screening, and therefore, development of a simple animal model for neuropathic pain has been desired.
On the other hand, an intrathecal administration method using a rodent, particularly a mouse, is known as a method which can be performed relatively simply without anesthetization (J. L. K. Hylden & G. L. Wilcox, Eur. J. Phammacol., 67: 313-316, 1980). It has also been reported that when NMDA (L. M. Aanonsen & G. L. Wilcox, J. Pharmacol. Exp. Ther., 243: 9-19, 1987) and substance P (J. L. K. Hylden & G. L. Wilcox, Brain Res., 217: 212-215, 1981) are intrathecally administered to mice, scratching, biting, and licking behavior, namely, SBL behavior, appears, suggesting the generation of pain. It has also been reported that by intrathecally administering (+)-4a-(3-hydroxyphenyl)-2-methyl-1,2,3,4,4a,5,12,12a-octahydro-trans-quinolino[2,3-g]isoquinoline to mice, hyperalgesia is generated (L. F. Tseng et al., J. Pharmacol. Exp. Ther., 280: 600-605, 1997). However, these animal models are exhibited as drug-induced nociceptive reaction models, and their usefulness as neuropathic pain models is not disclosed.
It is an object of the present invention to provide a therapeutic agent for neuropathic pain. It is another object of the present invention to provide a neuropathic pain animal model in which the therapeutic effect of a drug against neuropathic pain can be evaluated, to provide a method for evaluating an effective compound for treating neuropathic pain using the animal model, and to provide a compound obtained by the evaluation method.